Researchers have found a protein in the blood of human umbilical cords that improves memory and learning in old mice. The provocative finding joins a flurry of other recent, sometimes controversial work attempting to find factors that explain the apparent antiaging properties of young blood.
“These are exciting results,” says Sally Temple, scientific director of the Neural Stem Cell Institute in Rensselaer, New York, who was not involved with the work. She and others say the new finding suggests that this and other factors in young blood may have different, complementary effects on the aging brain.
Decades ago in somewhat grisly experiments, researchers found that sewing together the circulatory systems of an old and young mouse so that they shared the same blood supply rejuvenated the old animals. In 2014, as part of renewed interest in this unusual procedure, known as parabiosis, neuroscientist Tony Wyss-Coray’s lab at Stanford University in Palo Alto, California, reported that it could mimic some of the brain-boosting effects of parabiosis with injections of young mouse plasma, the cell-free part of blood.
Identifying the responsible factors in such blood is a challenge, however. Because mice are so tiny, it’s hard to collect enough mouse plasma to do biochemical and other analyses. As an alternative, Wyss-Coray’s lab recently tested the youngest human blood available—umbilical cord blood, which is traditionally thrown away after a birth but has become increasingly prized as physicians explore its therapeutic uses.
In the new work, Wyss-Coray’s group gave human cord blood plasma to mice of varying ages that had defective immune systems and so did not reject the foreign human tissue. Like young mouse plasma, human cord plasma injected every 4 days for 2 weeks into the circulation activated neurons in old mice’s hippocampi, where memories are made and stored. (This activation did not happen in the hippocampi of young mice treated with cord blood.) After the injections, the aging animals also navigated a maze more quickly and performed better on other tests of learning and memory, Wyss-Coray’s team reports today in Nature.
The team then looked for blood proteins that are abundant in human cords but decline in the general circulation with age. They ultimately homed in one called TIMP2, which was previously known to control the production of enzymes that chop up the matrix around cells and play a role in wound healing as well as the spread of cancer. (Its full name is tissue metallopeptidase inhibitor 2.) Old mice injected with mouse TIMP2 scored almost as well on memory tests as those given cord plasma, although they still didn’t match the cognitive skills of young mice, Wyss-Coray says. To help clinch its case for TIMP2, the Stanford group also showed that cord blood depleted of TIMP2 did nothing for old mice, and blocking TIMP2 in young mice impaired their memory.
The researchers’ search for antiaging factors did not point to another protein, GDF11, which some scientists have reported stimulates the growth of new blood vessels and neural stem cells in the brain. (Another claim—that GDF11 rejuvenates muscle—has been hotly contested by several labs, partly because their studies suggest GDF11 levels rise with age.)
But Wyss-Coray says the new study does not rule out a role for GDF11 in the brain. Harvard University neuroscientist Lee Rubin, who co-led the GDF11 brain study, says the new findings suggest “it isn’t just one thing. A lot of individual factors in blood can improve function.” Indeed, one might want to combine GDF11 and TIMP2 treatments to both generate new neurons and “get the most out of the cells that are there,” Temple suggests.
Some experts are less impressed by the study. Parabiosis researcher Irina Conboy of the University of California, Berkeley, notes that the paper doesn’t put the modest memory and learning improvements from TIMP2 in context by comparing them to, say, putting an old mouse on an exercise wheel, which can also improve cognitive function. Her own work suggests that the apparent antiaging effects of young blood may reflect the fact that it contains less of certain factors in old blood that her lab and others have reported contribute to aging.
Stanford has filed for patents on using TIMP2 to treat aging-associated conditions, and Alkahest, a company in San Carlos, California, that Wyss-Coray co-founded, plans to develop it. An Alkahest-sponsored trial at Stanford testing young human plasma as a treatment in 18 Alzheimer’s disease patients ended in January; results will be presented at a meeting in November, says Alkahest CEO Karoly Nikolich. (Rubin serves on Alkahest’s advisory board.) Meanwhile, some clinics are already offering young blood injections to reverse aging in people. But Wyss-Coray and others say such treatments are premature.